Pancreatic Ductal Adenocarcinoma (PDA) is a deadly malignancy. Early systemic spread and resistance to chemotherapy combine to make PDA one of the most dismal diagnoses in modern medicine. However, hundreds of experimental anticancer medicines are now in development and could be considered for Pancreatic Ductal Adenocarcinoma (PDA). Our studies to date show that PDA can be divided into distinct subclasses that differ biologically and that may respond differently to treatment. Our goal now is to advance treatment of PDA by refining molecular descriptors of Pancreatic Ductal Adenocarcinoma (PDA), identifying therapeutic agents on the Ras pathway that are effective in specific tumors, and eventually testing these in biomarker-marker guided clinical trials. This will be accomplished through work in two aims. Aim 1 will identify and model omic determinants of response to inhibitors of the Raf-MEK-ERK and PI3 Kinase/Akt pathways in a well characterized panel of PDA cell lines. Since we suspect that combined blockade will be required, we plan to test these agents both alone and in combination. Aim 2 will validate the biomarkers of sensitivity and resistance discovered in cell lines in a selected panel of PDA xenografts resected from patients and propagated and treated in the mouse. Biomarkers identifying specific responses in both preclinical systems will be tested in biomarker-guided clinical trials with inhibitors of the Ras pathway (beyond the scope of this proposal). Overall, we expect to test the hypothesis that biomarkers identified in efficient, preclinical model system screens will prospectively identify drug responsive and drug resistant patients in clinical trials. If true, this will allow experimental drugs now under development to be quickly tested for efficacy in subclasses of PDA and then moved quickly into trials in patient subpopulations in which they are most likely to be effective. This work is 100% relevant to Pancreatic Ductal Adenocarcinoma.